Biogenesis of macromolecular machines for post-transcriptional regulation of translation

Emory University, Atlanta GA

Investigators

Linked publications, trials & patents

Abstract

SUMMARY Non-coding RNAs (ncRNAs) are integral components of many essential RNA-protein complexes (RNPs) required for key cellular functions. As such, RNPs play a pivotal role in regulating gene expression and their dysregulation can result in pathological conditions including neurodevelopmental disorders, cancer, and neurodegeneration. The regulation of RNP formation governs the activity of crucial cellular machinery such as the telomerase, spliceosome, small nucleolar RNPs (snoRNPs), and the ribosome, yet much of this regulation remains poorly understood. My lab’s research focuses on revealing the molecular mechanisms that regulate RNP assemblies with an emphasis on snoRNPs and ribosomes. snoRNAs, an abundant class of small ncRNAs, play essential roles in guiding the processing and modifications of ribosomal RNAs (rRNAs), and their dysregulation is pathogenic. The deposition of numerous modifications on rRNA by snoRNPs is critical to control the quantity and quality protein synthesis. However, the significance of individual rRNA modification sites remains largely unknown to date. My research plan aims to understand the molecular connections between snoRNA regulation, rRNA modification pattern and translation regulation, using a multi-pronged technical platform that employs yeast genetics, biochemistry, advanced high throughput sequencing approaches, and mass spectrometry. This proposal builds on novel genetic tools and preliminary data to answer three fundamental questions: 1) How are snoRNA maturation and assembly coordinated with transcription? 2) How do rRNA modifications regulate translation? 3) How are snoRNAs and snoRNA- mediated rRNA modifications regulated? Understanding the intricate regulation of snoRNP biogenesis is crucial for revealing gene expression mechanisms that control translation and may offer potential therapeutic interventions in diseases linked to snoRNA dysregulation. Dissecting the contribution of rRNA modifications to translation will offer insights into faithful ribosome function and potential avenues for preventing translation dysregulation. Elucidating snoRNA regulation mechanisms across different biological contexts will reveal the common signatures and regulatory trends in this pathway that go awry in disease. Together, our studies will provide significant insights into the control of gene expression by snoRNAs with a potential to inform our view of how such dysregulations contribute to human disease.